Abstract
The unique cytokine responsiveness of virtual memory T (TVM) cells endows them with a potent capacity for bystander activation and effector function. Here, we investigated the antigen-independent impact of microbial infections on TVM cells. While Salmonella typhimurium or influenza A virus had no discernible effect, infection with lymphocytic choriomeningitis virus (LCMV) resulted in a rapid and profound depletion of TVM and true naive (TN) cells. Unlike TN cells, residual TVM cells exhibited a less differentiated phenotype and heightened T cell receptor (TCR) responsiveness, compared to cells from uninfected mice. Notably, these changes persisted into advanced age, with sustained reductions in TVM cell numbers and enhanced TCR sensitivity observed up to 18 months post infection, coincident with an attenuation of the senescent TVM cell phenotype. These findings reveal a previously unrecognized mechanism by which early-life pathogen exposure imprints long term changes on TVM cells, with broad implications for immune aging and lifelong immune competence.